Tissue niches and signals regulating lymphocyte maintenance

Principle Investigator

Scientific interest within the context of the graduate college

The innate immune system develops early in parallel with tissue formation, suggesting its role extends beyond host defense. In particular, tissue-resident innate lymphoid cells (ILCs) colonize tissues during fetal life and acquire effector functions prenatally acting as early-life sensors of the tissue environment. Our research focuses on understanding how the immune system, and ILCs in particular, contribute to the active maintenance of tissue homeostasis and how tissue-derived signals shape ILC differentiation, maintenance, and function. By defining these pathways, we aim to understand the molecular transition from a state of health to the earliest stages of pathology.

Project description

Lymphocytes comprise both adaptive and innate populations that arise from hematopoietic precursors. While these precursors originate in the fetal liver during embryogenesis and in the bone marrow after birth, accumulating evidence from our previous studies in mice and humans indicates that peripheral tissues function as active sites of lymphopoiesis, with local stromal, endothelial and epithelial cells providing nonredundant signals that support lymphocyte differentiation, maintenance, and function in situ.

In this context, the common y-chain cytokine IL-7 plays a central role in the survival, differentiation, and activation of both adaptive and innate lymphocyte populations. IL-7 signaling has established as key regulator of ILC homeostasis and IL-22 production, both of which are essential for maintaining the barrier integrity of the intestine. Using a combination of single-cell sequencing, in vitro systems, and in vivo analyses in established genetic mouse models, this project aims to define the cellular niches and molecular signals that sustain tissue-resident lymphocytes. we seek to determine how disruption of these circuits contributes to loss of tissue homeostasis and the development of immune-mediated pathology. To answer these questions, the project will have the following aims:

Aim 1: Define the intestinal ILC niche. To provide insights into the gene expression profiles and spatial organization of cells that facilitate health-maintaining interactions, we will characterize the IL-7-ILC niche during homeostatic balance. We aim to analyse unbiased single cell transcriptomic datasets of intestinal cell types (epithelial, endothelial, stromal cells, and ILCs) at steady-state and following environmental changes influenced by nutrient fluctuations along the proximal-distal axis of the small intestine. The goal is to identify the local cellular sources of IL-7 creating the anatomical niche required for the maintenance of intestinal ILCs. Methodological approaches will include bioinformatic analyses (R-Studio/Seurat), qPCR validations, and flow cytometry.

Aim 2: Elucidate the role of intestinal IL-7 sources for ILC composition. In our preliminary data, we have generated a conditional deletion of IL-7 selectively in the intestinal epithelium (Vil^Cre x Il7^fl/fl mice), where we observed a selective reduction of type 3 ILCs in the intestinal lamina propria, suggesting a non-redundant role for epithelial-derived IL-7 in maintaining tissue equilibrium. To gain a comprehensive understanding of the spatial requirements of IL-7, we will comparatively analyze lymphocyte subsets in mice that selectively ablate other sources of IL-7 in stromal (Pdgfra-cre) and endothelial (Cdh5-cre) compartments. All mouse lines are already established.

Overall, this project addresses the fundamental question of how tissue-resident immune cells act as actors of homeostasis. By comprehensively characterizing the small intestinal ILC niche, we aim to define the molecular requirements for “health” and identify the pathways that prevent the transition towards chronic inflammatory disease.

Application details

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